Alexander Disease

NORD gratefully acknowledges James E. Goldman, MD, PhD, Columbia University, for assistance in the preparation of this report.

Synonyms of Alexander Disease

dysmyelogenic leukodystrophy

dysmyelogenic leukodystrophy-megalobare

fibrinoid degeneration of astrocytes

fibrinoid leukodystrophy

hyaline panneuropathy

leukodystrophy with rosenthal fibers

megalencephaly with hyaline inclusion

megalencephaly with hyaline panneuropathy

General Discussion

Summary

Alexander disease is an extremely rare, usually progressive and fatal, neurological disorder. Initially it was detected most often during infancy or early childhood, but as better diagnostic tools have become available has been found to occur with similar frequency at all stages of life. Alexander disease has historically been included among the leukodystrophies--diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the "whitish" appearance of the so-called white matter of the brain. There is a marked deficit in myelin formation in most early onset patients with Alexander disease, and sometimes in later onset patients, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset individuals. Instead, the unifying feature among all Alexander disease patients is the presence of abnormal protein aggregates known as "Rosenthal fibers" throughout certain regions of the brain and spinal cord (central nervous system [CNS]). These aggregates occur inside astrocytes, a common cell type in the CNS that helps maintain a normal CNS environment. Accordingly, it is more appropriate to consider Alexander disease a disease of astrocytes (an astrogliopathy) than a white matter disease (leukodystrophy).

Introduction

Alexander disease is named after the physician who first described the condition in 1949 (WS Alexander).

Signs & Symptoms

Historically, three forms of Alexander disease have been described based on age of onset, Infantile, Juvenile and Adult; but an analysis of a large number of patients concluded that the disease is better described as having two forms, Type I, which generally has an onset by age 4, and Type II, which can have onset at any age, but primarily after age 4. Each type accounts for about half of the reported patients. Symptoms associated with the Type I form include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor impairment); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Additional features typically include progressive enlargement of the head (macrocephaly); abnormally increased muscle stiffness and restriction of movement (spasticity); lack of coordination (ataxia); and vomiting and difficulty swallowing, coughing, breathing or talking (bulbar and pseudobulbar signs). Nearly 90% of infantile patients display developmental problems and seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.

Patients with type II Alexander disease rarely show delay or regression of development, macrocephaly or seizures, and mental decline may develop slowly or not at all. Instead, about 50% display bulbar/pseudobulbar signs, about 75% have ataxia and about 33% spasticity. Because these symptoms are not specific, adult Alexander disease is sometimes confused with more common disorders such as multiple sclerosis or the presence of tumors. (For information on these diseases, see the related disorders section of this report.)

The two different forms of Alexander disease are generalizations rather than defined entities. In actuality there is an overlapping continuum of presentations; a one year old could present with symptoms more typical of a 10 years old, and vice-versa. However, in all cases the symptoms almost always worsen with time and eventually lead to death, with the downhill course generally (but not always) being swifter the earlier the onset.

Causes

About 95% of Alexander disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS. The cause of the other 5% of cases is not known.

The GFAP mutations are dominant. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Thus, Alexander patients have one mutant copy and one normal copy of the GFAP gene. The abnormal gene can be inherited from either parent or can be the result of a new mutation (change in the DNA of the gene). Most Alexander patients have a new mutation, indicating that neither of their parents has the mutation, but the mutation arose at some point during the development of sperm or ova or an embryo. As the disease becomes better diagnosed, familial cases, in which the disease is passed from one generation to the next, are being increasingly recognized. The risk of transmitting the disorder from an affected parent to an offspring is 50 percent for each pregnancy. The risk is the same for males and females.

How the GFAP mutations produce Alexander disease is not known. The Rosenthal fibers, which contain GFAP, accumulate throughout the surfaces of the brain (cerebral cortex), in the white matter of the brain, and in the lower regions of the brain (brainstem), and the spinal cord, and primarily appear under the innermost of the protective membranes (meninges) surrounding the brain and spinal cord (pia mater); under the lining of the fluid-filled cavities (ventricles) of the brain (subependymal regions); and around blood vessels (perivascular regions). Studies in mice indicate that the mutations act by producing a new, toxic effect, rather than by interfering with the normal function of GFAP. This toxic effect may be due to the presence of the Rosenthal fibers, or to the very large, abnormal amounts of GFAP that accumulate in Alexander astrocytes, or both. Astrocytes perform many critical functions in the CNS, and several of these are affected by the GFAP mutations, but the importance of these changes to the disease is not yet known.

Affected Populations

Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages.

Related Disorders

Symptoms of the following disorders can be similar to those of Alexander disease. Comparisons may be useful for a differential diagnosis:

Hydrocephalus is a condition in which the normal flow of cerebrospinal fluid (CSF) is restricted and the spaces in the brain (ventricles) become abnormally enlarged. Fluid accumulates beneath the skull and puts pressure on the brain. Hydrocephalus is characterized in children by an abnormally enlarged head (megalencephaly). The scalp may be thin and transparent, and the forehead may bulge (frontal bossing). Other symptoms of hydrocephalus may include convulsions, abnormal reflexes, a slowed heartbeat, headache, vomiting, weakness and/or problems with vision. (For more information on this disorder, choose “Hydrocephalus” as your search term in the Rare Disease Database.)

Multiple sclerosis is a chronic disorder of the CNS that causes the destruction of myelin, the fatty covering on axons (demyelination). The symptoms of this disease vary greatly and may include visual impairment, double vision and/or involuntary rhythmic movements of the eyes (nystagmus), impairment of speech, numbness or tingling sensations in the arms and legs, muscle weakness and/or difficulty walking, depending upon the area(s) of the CNS that Multiple Sclerosis affects. The symptoms of Multiple Sclerosis may be similar to those of Type II (late onset) Alexander disease. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)

Astrocytomas are brain tumors that can be either slowly growing (low-grade) or rapidly growing (malignant or high-grade) and are composed of astrocytes. Symptoms may vary according to the size, location, and growth rate of the tumor. Frequently the first symptom is a recurrent headache that is typically a result of increased pressure within the skull due to the growth of the tumor. Headaches may be accompanied by vomiting and/or personality changes. Other symptoms of low-grade or high-grade astrocytomas may include irritability, emotional instability, memory loss, intellectual impairment, convulsions, paralysis, bulbar and pseudobulbar signs, and seizures. The tumor cells in some types of low-grade astrocytomas contain Rosenthal fibers. (For more information on this disorder, choose “Astrocytoma” as your search term in the Rare Disease Database.)

Adrenoleukodystrophy is a form of leukodystrophy. It is a rare inherited metabolic disorder characterized by the accumulation of very long chain fatty acids in the brain that causes the progressive loss of myelin. This disorder also causes progressive degeneration of the adrenal gland (adrenal atrophy). Symptoms of the childhood form of adrenoleukodystrophy, which affects almost exclusively males and is inherited from the mother, may include loss of previously acquired intellectual skills, poor memory, loss of emotional control, a jerky uncoordinated walk (ataxia), and/or muscle weakness on one side of the body. Other symptoms may include difficulties with speech, hearing loss, and/or visual impairment. (For more information on this disorder, choose “Adrenoleukodystrophy” as your search term in the Rare Disease Database.)

Canavan leukodystrophy is another rare, inherited form of leukodystrophy characterized by the progressive deterioration of the CNS. Symptoms of this disorder may include floppiness, the loss of previously acquired mental and motor skills, poor head control, an abnormally enlarged head (megalencephaly) and/or blindness. As Canavan leukodystrophy progresses, there may be spastic muscle contractions in the arms and legs and paralysis. This disorder is caused by a chemical imbalance in the brain and symptoms typically appear in early infancy. It is autosomal recessive, so that one mutated gene is inherited from each parent, and it is most common in individuals of Jewish background. (For more information on this disorder, choose “Canavan” as your search term in the Rare Disease Database.)

Glutaricacidurias are rare, hereditary, metabolic disorders, caused by a deficiency or absence of an enzyme needed to break down certain chemicals in the body, resulting in the accumulation of several organic acids in the blood, urine, and organs. These disorders may have an extremely variable age of onset. Symptoms may include specific physical birth defects, a short life span, an enlarged head (macrocephaly), decreased muscle tone (hypotonia), nausea, vomiting, and low sugar (hypoglycemia) and excess acid in the blood. Affected individuals may also have involuntary movements of the trunk and limbs (dystonia or athetosis) and intellectual disability may also occur. (For more information on these disorders, choose “Glutaricaciduria I” and “Glutaricaciduria II” as your search terms in the Rare Disease Database.)

Krabbe leukodystrophy is a rare, inherited, lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids, galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe leukodystrophy is inherited as an autosomal recessive trait. (For more information on these disorders, choose “Leukodystrophy, Krabbe’s” as your search terms in the Rare Disease Database.)

Leigh syndrome is a rare, genetic, neurometabolic disorder characterized by the degeneration of the CNS. The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. (For more information on this disorder, choose “Leigh syndrome” as your search term in the Rare Disease Database.)

Metachromatic leukodystrophy is a rare, inherited, leukodystrophy characterized by the abnormal accumulation of a fatty-like substance (sphingolipid) in the brain and other tissues of the body. It affects both the central nervous system and the peripheral nervous system (peripheral nerves). Symptoms of this disorder may include muscle rigidity, visual impairment, and/or convulsions. Previously acquired physical and intellectual skills may be lost. This disorder may begin in infancy, adolescence, or adulthood. It is an autosomal recessive disorder. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database.)

Pelizaeus-Merzbacher disease is a rare, inherited, leukodystrophy characterized by the degeneration of the brain caused by the loss of myelin (demyelination). This disorder may begin in infancy or, less commonly, at older ages. The first symptoms in an infant include failure to thrive, developmental delays, muscle spasms, unsteadiness, weakness, and/or visual impairment. Deformities of the joints and seizures are sometimes seen. It is much more common in males than females and is inherited from the mother. (For more information on this disorder, choose “Pelizaeus-Merzbacher” as your search term in the Rare Disease Database.)
Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in cells of the central nervous system. Nerve cells are particularly severely affected. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30’s. (For more information on this disorder, choose “Tay Sachs disease” as your search term in the Rare Disease Database.)

Diagnosis

For many years a brain biopsy to determine the presence of Rosenthal fibers was required for the diagnosis of Alexander disease. However, even this procedure can be ambiguous, because Rosenthal fibers are also found in certain other disorders, such as tumors of astrocytes. More recently, MRI criteria have been developed that have a high degree of accuracy for diagnosing typical Type I (early onset) disease. These criteria have been less useful for some of the Type II cases, which have little or no white matter deficits in the brain, although abnormalities in the brainstem, cerebellum, and spinal cord can suggest the diagnosis. Accordingly, when making a diagnosis of Alexander disease, more common diseases that have similar symptoms for which tests are available should first be ruled out. These include adrenoleukodystrophy, Canavan’s disease, glutaricacidurias, Krabbe leukodystrophy, Leigh syndrome, metachromic leukodystrophy, Pelizaeus-Merzbacher and Tay-Sachs disease. A definitive diagnosis of Alexander disease rests on the identification of a GFAP mutation in the patient’s DNA, which can be obtained from a blood sample or a swab of the inside of the cheek. DNA analysis is provided by several commercial and research laboratories. However, since no GFAP mutation has been found in about 5% of known cases, a negative result does not completely rule out the disease. Presently, Alexander patients without a GFAP mutation can be definitively diagnosed only at autopsy by the presence of disseminated, large numbers of Rosenthal fibers.

Standard Therapies

Treatment

Treatment is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families. Fetal diagnosis is an option for a couple who have had a previously affected child.

Investigational Therapies

A few treatments have been performed on individual patients, but there have been no trials performed to determine if they are truly effective.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

Current research on Alexander disease is focused on identifying the genetic change in all cases and investigating the mechanism of how the mutations in the GFAP gene lead to the disease. Also being investigated is the exact composition of the Rosenthal fibers and the factors responsible for their formation and growth. Research is also underway to try to find ways to prevent the mutant GFAP from being made or accumulating. Together, these studies may eventually lead to new methods of diagnosis and, in time, to the development of new treatments for Alexander disease.
Families and individuals wanting to participate in studies on Alexander disease should contact the United Leukodystrophy Foundation (ULF) at (800) 728-5483.

Years Published

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